Dual action of cAMP-dependent protein kinase on granulocyte movement

Cell locomotion is a continuous cycle of integrin-dependent attachments and detachments along chemotactic gradients, driven by dynamic modulations of the actin network. Cyclic AMP (cAMP), which is known to be generated by N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP) receptors but not by beta2 integrins, was investigated as a coordinator of granulocyte locomotion. Elevation of cAMP by exposure to forskolin (100 microM) and 1-isobutyl-methylxanthine (IBMX; 100 microM) caused a marked reduction in beta2 integrin-induced polymerisation of actin, but had a less pronounced effect on the fMLP-induced actin response. Pretreatment of cells with rp-adenosine-3',5'-cyclic monophosphorothioate (rp-cAMPS; 50 microM), an inhibitor of the cAMP-dependent protein kinase (cAPK), resulted in a significant increase in the fMLP-induced actin polymerisation response. In agreement with the effect on filamentous actin (F-actin) forskolin and IBMX markedly suppressed the migration of granulocytes towards fMLP. Surprisingly enough, pretreatment of cells with rp-cAMPS inhibited cell movement to the same extent as forskolin and IBMX did. This dual action of cAMP on granulocyte migration suggest an important regulatory mechanism whereby the balance of this intracellular signal results in an optimal locomotory response.